Treatment for pulmonary hypertension

ABSTRACT

One embodiment relates to a method of treating pulmonary hypertension based upon co-administering to a subject in need thereof a pharmaceutically effective amount of an oral therapeutic agent for treating pulmonary hypertension and a pharmaceutically effective amount of an inhaled therapeutic agent for treating pulmonary hypertension. The benefit of the co-administration of these agents is to eliminate or reduce one or more side effects associated with mono-therapy of either agent, as well as one or more side effects associated with other administration routes such as subcutaneous or intravenous administration.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.13/047,033, filed Mar. 14, 2011, which claims priority from U.S.Provisional Application Ser. No. 61/282,659, filed Mar. 15, 2010.

All of the publications, patent applications and patents cited in thisspecification are incorporated herein by reference in their entirety.

BACKGROUND

Pulmonary Arterial Hypertension (PAH) is a condition in which thepressure in the lung circulation increases, eventually causing heartfailure and death. Although many causes and conditions are found to beassociated with PAH, many of them share in common several fundamentalpathophysiological features. One important feature among these processesis dysfunction of the endothelium, the internal cellular layer of allvessel walls, which is normally responsible for the production andmetabolism of a large array of substances that regulate vessel tone andrepair and inhibit clot formation. In the setting of PAH, endothelialdysfunction can lead to excessive production of deleterious substancesand impaired production of protective substances. Whether this is theprimary event in the development of PAH or part of a downstream cascaderemains unknown, but in either case it is an important factor in theprogressive vasoconstriction and vascular proliferation thatcharacterize the disease.

Thus, a need exists to develop an non-invasive therapeutic method totreat PAH.

SUMMARY

One embodiment is a method of treating pulmonary hypertension comprisingco-administering to a subject in need thereof a pharmaceuticallyeffective amount of an oral therapeutic agent for treating pulmonaryhypertension and a pharmaceutically effective amount of an inhaledtherapeutic agent for treating pulmonary hypertension.

An alternative embodiment provides a method of reducing a side effect ofa pulmonary hypertension treatment administered by subcutaneous orintravenous delivery, the method comprising co-administering to asubject in need thereof a pharmaceutically effective amount of an oraltherapeutic agent for treating pulmonary hypertension and apharmaceutically effective amount of an inhaled therapeutic agent fortreating pulmonary hypertension. The side effect can comprise systemichypotension, infection, thrombosis, site infusion pain, sudden infusioninterruption resulting in death, leg pain, or combinations thereof.

DETAILED DESCRIPTION

Unless otherwise specified, “a” or “an” means “one or more.”

The phrase “co-administer” as used herein means that the oraltherapeutic agent and the inhaled therapeutic agent are administered sothat their effective periods of biological activity will overlap in thesubject being treated.

One embodiment is a method of treating pulmonary hypertension comprisingco-administering to a subject in need thereof a pharmaceuticallyeffective amount of an oral therapeutic agent for treating pulmonaryhypertension and a pharmaceutically effective amount of an inhaledtherapeutic agent for treating pulmonary hypertension. In oneembodiment, the method reduces or eliminates at least one side effectassociated with mono-therapy of either the oral therapeutic agent or theinhaled therapeutic agent or at least one side effect associated withother treatments for pulmonary hypertension, such as subcutaneous orintravenous administration of such agents. For example, the side effectthat is eliminated or reduced by one embodiment of the presentlydescribed co-administration can include systemic hypotension, infection,thrombosis, site infusion pain, sudden infusion interruption resultingin death, leg pain, or combinations thereof.

The oral therapeutic agent for treating pulmonary hypertension can beselected from the group consisting of treprostinil, beraprost, bosentan,tadalafil, ambrisentan, macitentan, and sildenafil, or apharmaceutically acceptable salt or ester thereof. The oral therapeuticagent can also comprise a combination of these oral therapeutic agents.In one embodiment, the oral therapeutic agent is treprostinil or apharmaceutically acceptable salt or ester thereof. Suitable oralformulations of treprostinil are described in U.S. Pat. No. 7,384,978.In one embodiment, the oral therapeutic agent is a diethanolamine saltof treprostinil.

The inhaled therapeutic agent for treating pulmonary hypertension can beselected from the group consisting of treprostinil, Aviptadil, andiloprost, or a pharmaceutically acceptable salt or ester thereof. Theinhaled therapeutic agent can also comprise a combination of theseinhaled therapeutic agents. In one embodiment, the inhaled therapeuticagent is treprostinil or a pharmaceutically acceptable salt or esterthereof. Suitable inhaled formulations of treprostinil are described inU.S. Pat. No. 6,756,033. In one embodiment, the inhaled therapeuticagent is a sodium salt of treprostinil, which is commercially availableas Tyvaso®.

Abnormalities in three major endothelium-based pathways have beenidentified that serve as the basis for current treatments for PAH:

(1) Overproduction of endothelin. Endothelin is a vasoconstrictor andangiogenic substance that is produced in excess by the injuredendothelium in PAH. By blocking the receptor, endothelin-receptorantagonists (ERAs) neutralize the consequences of excessive endothelinsynthesis and produce clinical benefit.

(2) Underproduction of Nitric Oxide (NO). Nitric oxide is a potentvasodilator and inhibitor of vascular proliferation that is underproduced by the injured pulmonary vascular endothelium in PAH. Nitricoxide mediates these effects through cyclic GMP. By inhibiting thebreakdown of the enzyme that catabolizes cGMP, phosphodiesterase type-5inhibitors (PDE5i) such as sildenafil and tadalafil augment cGMP,thereby minimizing the impact of diminished NO activity in PAH, withresulting clinical benefit.

(3) Underproduction of prostacyclin. Prostaglandins are a heterogeneousfamily of endoperoxides that are produced in a variety of organ systemsand cells and have a number of important regulatory activities. In thevasculature, prostaglandin I2 (PGI₂, prostacyclin) is the most abundantand important prostacyclin produced by the endothelium, and serves as apotent vasodilator and inhibitor of growth and proliferation. As withNO, prostacyclin production by the pulmonary vascular endothelium isdiminished in the setting of PAH. Treatment of PAH with prostacyclin orits analogues has resulted in clinical benefit in PAH.

Of the various therapeutic approaches to treat PAH currently available,prostacyclin-based therapies are probably the most potent. For example,epoprostenol has been shown to improve survival in PAH. However, theseapproaches have several shortcomings. Specifically, “prostacyclinreplacement therapy” in PAH can be cumbersome, complex and dangerous,because of the pharmacology of the substance. Prostacyclin can beinactivated by a low pH, making it unsuitable for oral administrationbecause the low pH in the stomach can inactivate the compound.Furthermore, the half-life of prostacyclin in the blood is 3-5 minutes,which can demand continuous delivery in order to achieve a sustainedpharmacologic effect. Accordingly, epoprostenol (prostacyclin) should bedelivered by a continuous intravenous system, using an infusion pump anda permanent catheter inserted into the internal jugular or subclavianvein. Serious complications of this approach can include bloodstreaminfections, pump malfunction and catheter displacement, and can lead todeath.

Alternative approaches to prostacyclin-based therapy can be based on theuse of prostacyclin analogues, such as treprostinil and iloprost.Treprostinil, a longer-acting analogue, can be delivered intravenouslyand subcutaneously, although the former approach has the samelimitations as epoprostenol and the latter approach is limited by sitepain. The utilization of the lung as a site of delivery of prostacyclintherapy can be desirable: firstly, the lung vasculature is the site ofthe disease, and the proximity of the alveolar space to the vasculaturewould allow a greater concentration of drug at the disease site whengiven by the inhaled route as compared to the systemic route. Secondly,the large surface area of the lung and its vasculature can promote readyabsorption of drug into the systemic circulation to facilitate adequatedrug circulation and distribution. Both treprostinil and iloprost areapproved for inhaled delivery in PAH.

One limitation to inhaled prostanoid therapy in PAH alone is the abilityto deliver sufficient drug to equate to the amounts that can bedelivered by the parenteral route. Doses higher than those approved forinhaled iloprost or treprostinil are poorly tolerated due to localirritant effects in the airways and rapid uptake by the systemiccirculation, leading to intolerable side effects. Patients whodeteriorate with inhaled therapy may still respond to parenteraltherapy. This suggests that greater amounts of prostacyclin are neededfor these patients than can be effectively delivered by the inhaledroute alone.

Oral prostacyclin analogues, when used alone, can be less sensitive togastric pH, but their bioavailability can be poor. Beraprost, an oralprostacyclin analogue, can be limited in its ability to producelong-term benefit in PAH, largely due to the inability to deliversufficient drug into the circulation without producing intolerable localgastrointestinal side effects. Treprostinil is undergoing clinicaltrials as an orally-delivered prostacyclin analogue for PAH, buttolerability in doses intended to produce therapeutic blood levels hasbeen a limiting factor thus far.

The drawbacks of the treatments described above can be overcome byutilizing together two noninvasive portals for drug availability. Such acombination may be more efficacious than either route alone and may moreclosely approximate the efficacy of parenteral therapy without itsinherent toxicities. In particular, in one embodiment, a combination ofinhaled and oral delivery can be used. In one embodiment, at least twopharmaceutical compositions are delivered into a subject in need thereofby two different routes. The compositions can be the same or different.This combination can overcome the challenges facing prostacyclin-basedtherapy regarding the toxicity of parenteral delivery and he limitedability to deliver sufficient amounts of effective drug by thenonparenteral route.

Prostacyclin

The prostacyclin used in the therapy as described above can be any typeof prostacyclin (PGI₂), or an analogue thereof, known in the art, suchas any one in the eicosanoid family. In one embodiment, it can be anyprostacyclin and/or its analogue that is suitable to treat symptoms ofPAH. For example, the prostacyclin can be epoprostenol, treprostinil,iloprost, beraprost, an analogue of any thereof, or combinationsthereof. Beraprost can be used to effect vasodilation, which in turn canlower the blood pressure. Beraprost can also inhibit plateletaggregation.

Depending on the chosen delivery routes, different or samepharmaceutical compositions can be used in the embodiments. For example,in one embodiment of the therapy, a combination of beraprost andtreprostinil can be used. Specifically, in an embodiment of combinedtherapy, a first pharmaceutical composition delivered orally to asubject can comprise a prostacyclin, such as beraprost, and a secondpharmaceutical composition delivered by inhalation to a subject cancomprise prostacyclin, such as treprostinil.

Combined Therapy

In one embodiment, the co-administration can be carried out with anycombination of the oral and inhalation agent, as described above. Forexample, the oral delivery agent can be treprostinil, and the inhalationagent can be iloprost or Aviptadil. Preferably, in one embodiment, theinhaled therapeutic agent is Tyvaso or a pharmaceutically acceptablesalt or ester thereof, and the oral delivery agent is bosentan or apharmaceutically acceptable salt or ester thereof. In an alternativeembodiment, the inhaled therapeutic agent is Tyvaso or apharmaceutically acceptable salt or ester thereof, and the oral deliveryagent is sildenafil or a pharmaceutically acceptable salt or esterthereof.

The timing of the co-administration can vary, depending on the need ofthe patient. For example, the inhalation can be given four times a day,while the oral delivery can be given twice a day. For example, two ofthe oral dosings can coincide with two of the four inhalations.Alternatively, they do not need to coincident for the therapeuticbenefit. In an alternative embodiment, the inhalation can be given at afrequency other than four, such as one, two, three, five, or more, andthe oral delivery can be given at a frequency other than two, such asone, three, four, or more. As described above, the administration of theinhalation and oral delivery can overlap but does not need not.

Because almost all the blood circulates through the lungs, if the lungsbecome too constricted, the blood can have difficulty becoming properlyoxygenated and circulating through the lungs. This problem can beaggravated with pulmonary hypertension because the patients plateletsare also excessively adhesive to the pulmonary artery walls. Thus, thecombined effect of pulmonary artery constriction and platelet adhesiongreatly restricts blood flow through the pulmonary arteries, causing theright side of the heart to dilate as it tries to pump hard enough toforce blood through to the alveoli, ultimately resulting in right heartfailure. The presently described combined therapy can effectivelyeliminate or alleviate such problem.

In one embodiment, the combined therapy aims for the inhalation toprovide a potent vasodilation of the pulmonary arteries and for the oraldelivery to provide an desirable anti-platelet benefits, such aspreventing the platelets from becoming too adhesive to the pulmonaryarterioles. The dosage of the respective inhalation and oral deliveryagent can be optimized such that the inhalation can provide the maximumvasodilation effect on the patient's pulmonary arteries and the oraldelivery agent can provide the optimal anti-platelet benefit. Otherbenefits that can be provided by the present combined therapy, asdescribed before, can included systemic hypotension, infection,thrombosis, site infusion pain, sudden infusion interruption resultingin death, or leg pain.

The invention is further illustrated by, though in no way limited to,the following examples.

EXAMPLES Example 1

The new guideline for the diagnosis and treatment of PAH by Galie etal., 2009, which is hereby incorporated by reference in its entirety,emphasizes the need for investigating combination therapy. The resultspresented herein can be considered of medical importance because it willbe the first authorized combination therapy, fulfilling such medicalneed. Also, the pathogenesis of PAH is not fully understood, and therationale of a combination therapy targeted against two differentpathophysiological pathways appears plausible, especially in such afatal disease like PAH.

The combination of Tyvaso with either bosentan or sildenafil did notshow relevant pharmacokinetic (PK) interactions, increasing thefeasibility of such a combination where no dose adjustments areanticipated. This is in contrast to the PK interactions seen whensildenafil and bosentan, or tadalafil and bosentan are co-administered.The clinical experience with other prostanoids, in particular Remodulin(SC infusion) and Ventavis (inhalation), further supported the efficacyof treprostinil, though as a monotherapy. Tyvaso had one advantage ofeasier application than Remodulin, and the better compliance thereofthan with Ventavis was expected because of lesser daily applications.However, the target population who can benefit from this combinedtherapy can be better defined.

Patient status can be defined as: stable satisfactory, stable and notsatisfactory, or unstable and deteriorating. It can be assumed thatpatients recruited in TRIUMPH were “stable and not satisfactory”patients based on their 6-MWT of around 350 m and WHO FC III. If thisassumption is correct, then the combination therapy has not reallyachieved the desirable goal (i.e., stable and satisfactory status asdefined by the guidelines), but rather, it only improved exercisecapacity (and as proposed in the indication). This can be acceptable asoutlined before, after adequately defining the target population in asclinically stable patients. This also prevents using Tyvaso as asubstitute for epoprostenol, which is the first choice in the moresevere or unstable patients.

Considering that treprostinil is the same active constituent in both theSC preparation and the inhalation, several issues need to be addressed.Following the registration of Remodulin SC and through actual clinicalexperience, it appeared that the effective dose lied above that used inthe pivotal clinical studies, which was approximately 10 ng/kg/min. Thetypical range of Remodulin doses in current clinical practice isestimated to be approximately 20-100 ng/kg/min, with a mean of 53ng/kg/min. As observed by the present inventors, this need forcontinuous dose escalation with chronic use is only seen with continuousinfusion. One possible explanation for this difference is thefunctionality of the prostacyclin receptors in the face of continuousversus intermittent drug exposure, where tolerance is more seen with theformer method.

This explanation appears plausible, considering that the long termextension study was not actively controlled, and the need for doseescalation can not be excluded. In the long term open-label extensionTRIUMPH study, doses up to 72 μg q.i.d. have already been utilized. Thepossibility of using even higher doses, as is currently practiced withRemodulin, can not be excluded. However, an adequate warning should beadded to remedy any lack of safety data. In conclusion, the efficacy oftreprostinil inhalation is based on the results of one pivotal trial,which showed a statistically significant increase in the 6-MWD inpatients administered treprostinil inhalation on top of bosentan orsildenafil. The combination fulfils an unmet medical need for acombination therapy, but the target group should be defined asclinically stable patients.

Example 2

The placebo-controlled phase of TRIUMPH showed that administration ofTyvaso on top of bosentan or sildenafil resulted in a significant medianimprovement of +21.6 meters in 6-MWD, as compared to +3.0 meters in theplacebo group. This was accompanied by improvement in the level ofNT-Pro-BNP, and in some scores of Quality of Life, but not in thefunctional class or time to clinical worsening. With a study duration of12 weeks, no significant effects in the latter endpoints were actuallyexpected.

Long term data support the long term durability of the results, thoughthey are difficult to interpret considering the uncontrolled design.

Tyvaso is the first application for combination therapy in themanagement of PAH. The documented increase in the 6-MWT is in line withthat shown with other combinations, in particular iloprost on existingbosentan therapy, sildenafil on top of epoprostenol, and tadalafil ontop of bosentan. The current results is considered of medical importancebecause it will be the first authorized combination therapy, fulfillingsuch medical need. Also the pathogenesis of PAH is not fully understoodand the rationale of a combination therapy targeting two differentpathophyisiological pathways appears plausible, especially in a fataldisease like PAH. The combination of Tyvaso with bosentan or sildenafildid not show relevant PK interactions, increasing the feasibility ofsuch a combination where no dose adjustments are anticipated. This iscontrast with the PK interactions seen when sildenafil and bosentan, ortadalafil and bosentan are co-administered. The clinical experience withother prostanoids in particular Remodulin (SC infusion) and Ventavis(inhalation) lends further support to the efficacy of treprostinil,though as a monotherapy. Tyvaso has an obvious advantage of easierapplication than Remodulin, and the present inventors expect bettercompliance than with Ventavis because of lesser daily applications.However, the target group of this combination therapy with Tyvaso shouldbe adequately defined as clinically stable patients, to prevent usingTyvaso as a substitute for epoprostenol which is specifically indicatedfor unstable patients.

The combination of Tyvaso with either bosentan or sildenafil (two oralPAH treatments) appears feasible as it targets two differentpathophysiological pathways. No PK interactions are seen. The gain inthe 6 MWT is moderate but in line with other combinations. Efficacy ofTyvaso is also supported by the efficacy previously shown for Remodulinor Ventavis. It promises in addition easier and less frequentapplication. However, as with other prostanoids, tolerance to the effectand the need of higher doses with chronic administration can not beexcluded.

No conclusions is yet drawn regarding the superiority of Tyvaso whencombined with bosentan compared to when it is combined with sildenafil.The combination of Tyvaso with either drug is acceptable, provided thatthe target group is adequately defined as clinically stable patients andthe expected treatment goals are clear.

Example 3

Remodulin® (treprostinil sodium) Injection has been approved in theUnited States and other countries for continuous subcutaneous andintravenous infusion for the treatment of pulmonary arterialhypertension (PAH). Tyvaso® (treprostinil) Inhalation Solution has alsobeen approved in the United States for the treatment of PAH.Treprostinil is a chemically stable tricyclic benzindene analogue ofprostacyclin (PGI2) that exhibits platelet anti-aggregatory and potentvasodilatory effects. UT-15C is the diethanolamine salt of treprostinil,currently in development by United Therapeutics Corporation as asustained release oral treatment option for PAH.

Summary: Given that the identical bioactive molecule, treprostinil, isdelivered by each of these routes of administration, the present studywas undertaken to help determine whether combined treatment with oralplus inhaled treprostinil (UT-15C plus Tyvaso) may have additive effectson cardiopulmonary hemodynamics in a rat PAH model. It would beclinically desirable if combined oral plus inhaled dosing could prevent,or delay the time to initiation of parenteral therapy, which is the mostinvasive route and is typically reserved for the advanced disease.

This study utilized administration of a thromboxane agonist to elevatepulmonary artery pressure (PAP) in the rat as a model for PAH.Treprostinil was administered to the rats by oral gavage (UT-15C),nose-only inhalation (Tyvaso) or in a combined oral+inhalation regimen,followed by PAP assessment. In this initial experiment in a newlydeveloped rodent PAH model to monitor PAP measurements duringtreprostinil therapy, treprostinil therapy generally reduce PAP duringthe PAH condition, regardless of the route of administration. Also,additional PAP reduction was observed (either in magnitude or duration)when oral treprostinil was administered in addition to a low dose ofinhaled treprostinil as part of a combination dosing regimen.

Experimental Design: For this study, a rat model of acute PAH wasdeveloped with the ability to measure real-time PAP by telemetry from acatheter surgically implanted into the rat pulmonary artery. To inducePAH in this model, a 15 minute intravenous (IV) infusion of thethromboxane agoinst, U44069, was administered, and PAP was monitored andrecorded every 5 seconds.

To establish this model, initial testing and optimization of theconcentration and infusion rate of the U-44069 was performed to bestachieve elevated PAP. Preliminary dose range-finding assessments of theefficacy of oral or inhaled treprostinil at doses that have previouslybeen shown to have limited toxicities in GLP preclinical animal studieswere also performed. Following the preliminary individual oral andinhaled treprostinil range-finding studies, a combination administrationof oral+inhaled treprostinil was performed. The study design and resultsare described below.

Study Design Target Dose Formulation Target Dose Duration of LevelConcentration Level^(A) inhalation Number of Group Group For gavage forGavage For inhalation exposure Animals Number Designation (mg/kg/day)(mg/mL) (μg/kg/day) (min) Male 1 Low Dose 5 1 5.26 9 2 2 Mid Dose 10 210.6 17 2 3 High Dose 15 3 34.1 55 2 ^(A)Target dose levels arecalculated based on an estimated body weight of 0.3 kg.IV dose of U-44069 to elevate PAP:

The animals received U-44069 (0.5 mg/mL) at a dose rate of 10 mL/kg/hrfor 15 minutes for a total dose of 1.25 mg/kg/dose. The animals received3 to 4 IV doses/session, as detailed below.

Dose 1, oral gavage:

-   -   1. Animals were treated as follows:    -   2. IV for 15 minutes    -   3. Oral gavage, as soon as practicable following the 15-minute        infusion    -   4. 1 hour following gavage, IV for 15 minutes.    -   5. 2 hours following gavage, IV for 15 minutes        Dose 2, inhalation:

Animals were treated as follows:

-   -   1. IV for 15 minutes    -   2. Inhalation exposure, as soon as practicable following the        15-minute infusion    -   3. Approximately 5 minutes after inhalation completion, IV for        15 minutes.    -   4. 1 hour later, IV for 15 minutes        Dose 3, inhalation and oral gavage:

Animals were treated as follows:

-   -   1. IV for 15 minutes    -   2. Oral gavage, as soon as practicable following the 15-minute        infusion    -   3. Inhalation exposure, as soon as practicable following oral        gavage. All animals were exposed to the low dose (5.26 μg/kg).    -   4. Approximately 5 minutes after inhalation completion, IV for        15 minutes.    -   5. 1 hour later, IV for 15 minutes    -   6. 2 hours after oral gavage, IV for 15 minutes for 2 animals (1        low and 1 high oral dose)        Inhaled, Oral and Combination Treprostinil Dosing Results:

The following figure summarizes the results from the separate routes orcombination administration of treprostinil for the individualtelemetered animals. Maximum PAP values during the U-44069 infusions areexpressed as the % change from baseline (untreated) PAP.

-   -   On all reported occasions, the IV dosing of U-44069 increased        the PAP to at least 150% of the baseline, except for        animal 2001. However, it should be noted that the baseline        pressures for this animal are significantly higher than the        other animals.    -   Inhalation—5.26, 10.6, or 34.1 μg/kg/day: PAP was reduced to        approximately 120% the baseline following inhalation exposure at        all dose levels and was relatively stable over the 15-minute        injection. Following an additional IV injection of U-44069        1-hour after the completion of inhalation exposures, PAP was        significantly increased when compared to the Immediately Post        Dosing (IPD) values. At 1 hr post dosing (PD), PAP was        significantly increased when compared to the IPD values.    -   Oral gavage—5, 10, or 15 mg/kg/dose: decreases in PAP were        generally observed in a dose-related fashion at both the 1 hr PD        and 2 hr PD time points evaluated.    -   Combination Dosing—low dose inhaled (5.26 μg/kg/day)+low (5        mg/kg/dose), mid (10 mg/kg/dose), or high (5 mg/kg/dose) dose        oral gavage:        -   Group 1: Combination dosing of treprostinil exhibited a            sustained effect to 1 hr that was not seen when only low            dose inhaled treprostinil was administered. The sustained            reduction in PAP was likely more apparent in animal #1001            because the U-44069 had a greater pharmacological effect on            increasing PAP in this animal, and the action of            treprostinil to reduce PAP toward baseline values was more            apparent.        -   Group 2: For both animals, the PAP decrease was equivalent            or greater at the IPD time point, even though the low            inhaled dose (5.26 μg/kg/day) in the combination dosing            regimen is half of the individual mid-dose inhalation (10.6            μg/kg/day). For animal #2002 the increased PAP reduction was            sustained out to 1 hr PD and this reduction was even greater            than the individual oral dose. For animal #2001, the            reduction in PAP was greater (possibly additive) at the IPD            and slightly lower at 1 hr PD when compared to the            individual mid dose inhalation, although it was slightly            higher than the oral alone at 1 hr PD. This could be due to            variability in this animal. In addition, the U-44069 had a            greater pharmacological effect on increasing PAP in animal            #2002, which likely allowed for a greater action of            treprostinil to reduce PAP toward baseline values.        -   Group 3: Even though the low inhaled dose (5.26 μg/kg/day)            in the combination dosing regimen is less than 6× the high            dose (34.1 μg/kg/day) administered in the individual            inhalation condition, the ability of the combination dosing            regimen to reduce PAP at the IPD time point was equivalent            (#3001) or greater (#3002) than the individual high dose            inhalation, and this effect was sustained out to 1 hr PD.            The U-44069 had a greater pharmacological effect on            increasing PAP in animal #3002 during the combination dosing            component, which likely allowed treprostinil to better            reduce PAP at the IPD time point.        -   For combination dosing, it also appeared that animals that            responded well to treprostinil via inhalation and not as            well to treprostinil via oral gavage (#1001 and #2002) were            better able to show a sustained effect at 1 hr PD during the            inhalation therapy. More refined dose range-finding studies            (dosing and time points for PAP measurements) will help us            to better understand this observation.

Although the foregoing refers to particular preferred embodiments, itwill be understood that the present invention is not so limited. It willoccur to those of ordinary skill in the art that various modificationsmay be made to the disclosed embodiments and that such modifications areintended to be within the scope of the present invention.

What is claimed is:
 1. A method of treating pulmonary hypertensioncomprising co-administering to a subject in need thereof apharmaceutically effective amount of an oral therapeutic agent fortreating pulmonary hypertension and a pharmaceutically effective amountof an inhaled therapeutic agent for treating pulmonary hypertension,wherein the oral therapeutic agent is beraprost or a pharmaceuticallyacceptable salt thereof administered orally and the inhaled therapeuticagent is treprostinil or a pharmaceutically acceptable salt thereofadministered by inhalation.
 2. The method of claim 1, wherein thesubject is a human being.
 3. The method of claim 1, wherein the inhaledtherapeutic agent is sodium salt of treprostinil.
 4. The method of claim1, wherein the co-administration delays the time to initiation ofparenteral therapy for pulmonary hypertension in comparison to therapywith either an oral or inhaled therapeutic agent for pulmonaryhypertension used alone.
 5. A method of reducing a side effect of apulmonary hypertension treatment administered by subcutaneous orintravenous delivery, comprising co-administering to a subject in needthereof a pharmaceutically effective amount of an oral therapeutic agentfor treating pulmonary hypertension and a pharmaceutically effectiveamount of an inhaled therapeutic agent for treating pulmonaryhypertension, wherein the oral therapeutic agent is beraprost or apharmaceutically acceptable salt thereof administered orally and theinhaled therapeutic agent is treprostinil or a pharmaceuticallyacceptable salt thereof administered by inhalation.
 6. The method ofclaim 5, wherein the subject is a human being.
 7. The method of claim 5,wherein the inhaled therapeutic agent is a sodium salt of treprostinil.8. The method of claim 5, wherein the side effect comprises systemichypotension, infection, thrombosis, site infusion pain, sudden infusioninterruption resulting in death, leg pain, or combinations thereof.